Ionic Cocrystals of Racemic and Enantiopure ... - ACS Publications

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Ionic Cocrystals of Racemic and Enantiopure Histidine: An Intriguing Case of Homochiral Preference Dario Braga,* Lorenzo Degli Esposti, Katia Rubini, Oleksii Shemchuk, and Fabrizia Grepioni Dipartimento di Chimica “G. Ciamician”, Università degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy S Supporting Information *

ABSTRACT: Ionic cocrystals (ICC) of L- and DL-histidine with lithium halides (LiCl, LiBr, LiI) have been prepared by solid state and solution methods, and structurally characterized in order to compare the behavior of enantiopure and racemic crystals in the interaction with inorganic salts. It has been shown that the lithium cations interact selectively with enantiomers of one handedness only, to the extent that the crystals obtained with racemic DL-histidine can be described as a special type of cocrystals made of enantiopure L-histidine and D-histidine chains of the same type as those obtained with enantiopure L-histidine. This chiral preference is even more noticeable in the ICC obtained from DL-histidine and LiI, which is actually a conglomerate of L- and D-ICCs. It is also reported that attempts to prepare ICCs with other alkali/alkaline earth halides invariably yield crystals of the less stable polymorph of L-histidine.

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INTRODUCTION Chiral resolution is one of the “evergreen” topics of research focus, because of the need of using enantiopure materials in all areas that interface with the biological sciences, especially the development of new drugs. The human organism is intrinsically chiral, and particular attention must be given to the biological behavior of the enantiomeric forms of the same active pharmaceutical ingredient (API). In fact, enantiomers may have either dramatically different efficacies or even be antagonists for the same receptor. Some other possible differences can be in pharmacodynamics, where one enantiomer can be completely inactive toward the desired target receptors and/or have a different biological activity; the same is also true for a racemic API versus an enantiopure one.1−3 Besides the biological reasons mentioned above, the need to specify the enantiopurity of an API is also required by the regulating agency, e.g., FDA.4 Moreover, the use of an enantiopure API can have some economic advantages, as it allows a 100% active pharmacological formulation. Crystal engineering5−12 provides the conceptual frame to develop solid state strategies for chiral resolution via selective interactions between molecules. This has been applied in the booming field of cocrystals, whereby two or more molecules forming stable solids at ambient conditions are brought together in the same crystal structure.13−16 Cocrystals synthesis allows one to modify the physicochemical properties (stability, bioavailability, solubility, hygroscopicity, etc.) of a specific crystalline solid, e.g., an API, with positive effects on pharmaceutical formulations17−27 and implications on intellectual property issues. Cocrystallization also offers a viable route to the resolution of racemic mixtures by using enantiopure coformers. The basic idea is that the reaction (whether in solution or in the solid state) of a racemic R,S molecule, possibly an R,S-API, with an © 2016 American Chemical Society

enantiopure coformer, say an R-coformer, might lead to R-API/ R-coformer and S-API/R-coformer aggregates possessing different structures and different physicochemical properties that could be used for resolution. If the reaction is between a racemic API and an acid/base enantiopure species capable of hydrogen bonding donor/acceptor interaction via proton transfer, different salts will be obtained depending on the chirality of the component ions. The two cases are depicted in Scheme 1. Scheme 1. Chiral Resolution via Formation of a Diastereomeric Cocrystal (Top) and Salt (Bottom)

This approach has been used by Leyssens et al. to resolve a racemic solution of the API leviracetam by using (S)-mandelic acid as a coformer.28 The same authors estimated that about 85% of the cocrystals between chiral molecules could behave enantioselectively and supplied a method for screening for cocrystallization by construction of ternary and quaternary diagrams.29,30 Other examples are the induction of an enantiomeric enrichment of DL-arginine by cocrystallization with fumaric acid31 and the development of a resolution procedure on praziquantel by cocrystallization with L-malic acid.32 Received: September 27, 2016 Revised: October 29, 2016 Published: November 11, 2016 7263

DOI: 10.1021/acs.cgd.6b01426 Cryst. Growth Des. 2016, 16, 7263−7270

Crystal Growth & Design

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Recently, it has been shown that ionic cocrystals can also be obtained when organic molecules, including APIs, are cocrystallized with inorganic salts.33−37 In ionic cocrystals (ICCs) the dominant interactions have an electrostatic nature, with the possible additional contribution of hydrogen bonds between common donor and acceptors (OH, NH, O, N, etc.) and between HB donors and anions (OH···Cl−, NH···Br−, etc.).35−37 This is also the case of many hydrogen bonded salts.38 Because of the strong Coulombic interactions, the change in physicochemical properties with respect to those of the organic conformer associated with ICC formation is expectedly more dramatic than with most molecular cocrystals. Moreover, since some inorganic salts are admitted by the pharmacopoeias, they are suitable coformers.35−37 In the cases of the ICCs of LiCl with drugs of the racetam family, the inorganic component is also an API, so both the constituents of the ionic cocrystal can, in principle, possess pharmacological activity.39,40 The idea developed in this paper combines the issue of chirality with that of ICC formation. Herein we explore the behavior of the amino acid histidine, which is also a prodrug, toward ICC formation, using enantiopure L-histidine and racemic D,L-histidine (L-His and D,L-His in the following, respectively) as reactants in mechanochemical and solution preparations of cocrystals with alkali halides. L-Histidine is known in two polymorphic forms, the thermodynamically stable orthorhombic polymorph41 and a metastable monoclinic one,42,43 while only one crystal form is known for DL-histidine.44,45 All crystal forms contain the amino acid in its zwitterionic form (see Scheme 2).

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EXPERIMENTAL SECTION

All reagents were purchased from Sigma-Aldrich and used without further purification; ultrapure water, produced with a Millipore Milli-Q instrument, was used as a solvent. Solution Synthesis. Histidine (0.5 mmol) and the alkali halide (0.5 mmol) were dissolved in 4 mL of water and left to evaporate in a thermal bath at ca. 50 °C. In the case of lithium salts crystalline L-His·LiCl·H2O, DL-His·LiCl·1.5H2O, L-His·LiBr·H2O, DL-His·LiBr· 1.5H2O, and L-His·LiI·1.5H2O were obtained. Solid-State Synthesis. The lithium halides ICCs were obtained also by manually kneading histidine (0.5 mmol) and the lithium salt (0.5 mmol) in an agate mortar for 30 min with a drop of water; all reactions were quantitative. In view of the high hygroscopicity of the Li salts, no attempt was made with other solvents. TGA. TGA measurements were performed with a PerkinElmer TGA7 in the temperature range 40−500 °C under N2 gas flow at a heating rate of 5.00 °C min−1. Single Crystal X-ray Diffraction. Single crystal X-ray diffraction data were collected at room temperature with an Oxford Diffraction X’Calibur equipped with a graphite monochromator and a CCD detector. Mo−Kα radiation (λ = 0.71073 Å) was used. Unit cell parameters for all compounds discussed herein are collected in Table 1. Single crystal data were collected for all compounds. However, those obtained for DL-His·LiCl·1.5H2O have not been deposited with the CCDC because of the overall poor quality of the diffraction data and of the high R factor. Nonetheless the refinement confirmed the isostructurality with DL-His·LiBr·1.5H2O, which was also confirmed by comparing the observed powder diffractograms for the two structures (see Supporting Information). SHELX9746 was used for structure solution and refinement based on F2. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms bound to carbon atoms were added in calculated positions. Hydrogen atoms bound to nitrogen and oxygen atoms were either located from a Fourier map or added in calculated position, and their position was refined riding on their C/N/O atoms. The software Mercury 3.847−50 and VESTA 3.3.851 have been used to analyze and represent the crystal packing, and also (Mercury) to simulate powder patterns based on single crystal data.47−50 X-ray Diffraction from Powder. For phase identification purposes, X-ray diffraction patterns were collected on a PANalytical X’Pert Pro automated diffractometer equipped with an X’Celerator detector in Bragg−Brentano geometry, using Cu−Kα radiation (λ = 1.5418 Å) without monochromator in the 2θ range between 3° and 50° (step size: 0.033°; time/step: 20 s; Soller slit: 0,04 rad; antiscatter slit: 1/2; divergence slit: 1/2; 40 mA*40 kV). Variable Temperature X-ray Diffraction. X-ray powder diffractograms in the 2θ range between 3° and 50° were collected on a PANalytical X’Pert PRO automated diffractometer equipped with an X’Celerator detector and an Anton Paar TTK 450 system for measurements at controlled temperature. The data were collected in open air in Bragg−Brentano geometry using Cu Kα radiation without a monochromator. Thermal programs were selected on the basis of thermogravimetric measurement results.

Scheme 2. Histidine Zwitterion

Each crystalline product discussed in the following section has been characterized by powder X-ray diffraction (PXRD), and all structures have been determined by single crystal X-ray diffraction (SCXRD). The products were also thermally characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Variable temperature analysis was employed with hydrated ionic cocrystals, to determine if the dehydration process would lead to decomposition, amorphization, or formation of stable anhydrous crystalline phases. Table 1. Unit Cell Parameters of the Histidine ICCs ICC L-His·LiCl·H2O a DL-His·LiCl·1.5H2O

L-His·LiBr·H2O DL-His·LiBr·1.5H2O L-His·LiI·1.5H2O DL-His·LiI·1.5H2O

b

a (Å)

b (Å)

c (Å)

β (deg)

V (Å3)

space group

5.1440(5) 22.654(5) 5.1597(5) 23.185(2) 18.248(1) 18.265(5)

10.3003(7) 5.1413(10) 10.401(1) 5.1556(4) 5.1245(4) 5.128(2)

19.423(2) 19.693(4) 20.189(2) 20.002(1) 12.9174(9) 12.927(4)

90 115.09(3) 90 115.459(8) 105.505(7) 105.516(4)

1029.1(2) 2077.2(9) 1083.40 2158.80 1163.98 1166.56

P212121 C 2/c P212121 C 2/c C2 C2

a

Single crystal data quality for DL-His·LiCl·1.5H2O, though not sufficient for publication, still allowed cell parameters and space group determination. Cell parameters and space group from powder data: the crystal is actually a conglomerate of L-His·LiI·1.5H2O and D-His·LiI·1.5H2O (see Results and Discussion). b

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RESULTS AND DISCUSSION All compounds discussed in the following were prepared by both kneading (also called liquid assisted grinding, LAG)52−55 and fast solvent evaporation. Both methods yielded consistently the same products. Obviously, solvent evaporation was the method of choice to obtain single crystals of suitable quality; powders patterns calculated on the basis of the single crystal structure could in turn be used for comparison with experimental patterns collected on the bulk. All the obtained ICCs are colorless, thin needles (see Figure 1).

diffraction pattern associated with the dehydration process. The powder pattern measured at 210 °C is most likely the pattern of the anhydrous ICC L-His·LiCl; this solid, however, is unstable, and reverts quickly to L-His·LiCl·H2O at room temperature. Similar behavior had been observed previously with the ICC of lithium chloride and piracetam.39 Isomorphous ICCs of Racemic Histidine with LiCl and LiBr: DL-His·LiCl·1.5H2O and DL-His·LiBr·1.5H2O. The ionic cocrystal obtained with DL-histidine and LiCl has the formula DL-His·LiCl·1.5H2O. Unfortunately, in spite of numerous attempts, no single crystal could be obtained of sufficiently good quality for publication. However, preliminary single crystal data (see Table 1) clearly indicate that DL-His·LiCl·1.5H2O is isomorphous with DL-His·LiBr·1.5H2O, which yielded crystals suitable for structural description and will thus be used in the following. Surprisingly, even though the space group C2/c is centrosymmetric, the crystal packing is extremely similar to that observed for crystalline L-His·LiCl·H2O in the non-centrosymmetric space group P212121, with lithium cations tetrahedrally coordinated to three histidine molecules of the same chirality and one water molecule. The tetrahedra form infinite chains along the a-axis, exactly as in the L-His·LiCl·H2O crystal (see Figure 5a). In crystalline DL-His·LiBr·1.5H2O lithium-histidine chains of opposed chirality alternate (see violet and orange chains in Figure 5b). A striking feature of the crystal of DL-His· LiBr·1.5H2O is, therefore, that the individual lithium− histidine chains are enantiopure. Figure 5c shows an overlap of the lithium coordination tetrahedron in the L- and DL-ICCs. Note that DL-His·LiBr·1.5H2O has an additional (half) water molecule per formula unit with respect to its enantiopure counterpart; this water molecule lies on a crystallographic special position between the layers and is at hydrogen bonding distance to the chloride ions. As in the case of L-His·LiCl·H2O, the calculated powder pattern matches the experimental one, as reported in Figure 6. A simple way to look at the racemic crystals of isomorphous DL-His·LiCl·1.5H2O and DL-His·LiBr·1.5H2O, therefore, is considering them special “cocrystals” of L-His·LiCl/Br·H2O and D-His·LiCl/Br·H2O, with the intervention of an additional water molecule to “glue” them together: see Scheme 3 for a pictorial representation. Thermogravimetric analyses on crystalline DL-His·LiCl·1.5H2O and DL-His·LiBr·1.5H2O (see Figures S2 and S4, respectively) show weight losses between room temperature and 80 °C, and one between ca. 90 and 200 °C, most likely due to the stepwise loss of the non coordinated water molecule first, followed by the loss of the water molecule coordinated to the lithium cation. The variable temperature powder diffraction patterns (Figures S8 and S10 for DL-His·LiCl·H2O and DL-His·LiBr· H2O, respectively) show changes that can be associated with the two dehydrations steps. The anhydrous cocrystal is unstable and rehydrates when brought back to room temperature. ICCs of Enantiopure and Racemic Histidine with LiI: L-His·LiI·1.5H2O and a Case of Chiral Resolution. A remarkable variation in this pattern is shown by the ionic cocrystals of L-histidine and racemic DL-histidine with lithium iodide. While the enantiopure ICC, L-His·LiI·1.5H2O, is quasiisostructural with those obtained with LiCl and LiBr, the crystal obtained with DL-histidine turns out to be a conglomerate of crystals of enantiopure L-histidine with LiI and of enantiopure D-histidine with LiI. The L-histidine cocrystal has the formula L-His·LiI·1.5H2O, hence with a slightly higher water content with respect to the

Figure 1. Ionic cocrystals of histidine with lithium halides are all colorless and thin needles: here crystals of DL-His·LiCl·1.5H2O are shown as a representative example.

Isomorphous ICCs of Enantiopure Histidine with LiCl: and L-His·LiBr·H2O. The ionic cocrystals obtained with L-histidine and lithium chloride or bromide, L-His·LiCl·H2O and L-His·LiBr·H2O, are isomorphous and will be discussed together. In their crystals the lithium cation assumes a tetrahedral coordination, interacting with three oxygens from three different molecules of L-His and with a fourth oxygen from a water molecule (see Figure 2a); each of the three histidines interacts in turn with three Li+: the resulting stoichiometry is 1:1, and the main crystalline feature is an infinite chain of tetrahedra sharing vertices and bridged in pairs by L-His molecules (see Figure 2b,c). The chains extend parallel to the a-axis and lie side by side, as shown in Figure 2d. With this kind of packing, the hydrophobic regions (the aromatic rings) are at close contact and away from the polar region. The chloride ions are interposed between the layers. Each ammonium group interacts via hydrogen bonds with two chloride ions and with the pyridinic nitrogen of a neighboring histidine of the same chain, while the imidazolic nitrogen is hydrogen bonded with the water molecule of a neighboring chain, which, in turn, is at a close distance to two chloride ions. The powder patterns for L-His·LiCl·H2O (see Figure 3) and L-His·LiBr·H2O (see Figure S6), calculated on the basis of the single crystal structures, match the experimental ones, confirming that the single crystal structures are representative of those of the bulk. Thermal analysis on L-His·LiCl·H2O and L-His·LiBr·H2O confirms the monohydrate nature of these crystalline materials, showing a weight loss, in the ranges 150−240 °C and 130−230 °C for the chloride and bromide ICCs, respectively, which can be attributed to the removal of one water molecule per formula unit. Variable temperature powder diffraction measurements on the two systems (see Figures 4 and S7 for the chloride ICC, and Figure S9 for the bromide ICC) show a change in the L-His·LiCl·H2O

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Figure 2. (a) The lithium cation tetrahedral coordination in L-His·LiCl·H2O (the packing arrangement is exactly the same in isomorphous L-His· LiBr·H2O). (b) Side-view of the infinite chain of lithium coordination tetrahedra extending along the crystallographic a-axis; (c) the same chain is projected down the a-axis. (d) Projection of the crystal packing in the bc-plane [Owater in blue, Cl− in green; hydrogen bonds not shown for clarity].

other enantiopure systems of formula L-His·LiCl·H2O and L-His·LiBr·H2O, but the crystal packing is essentially the same, i.e., L-His·LiI·1.5H2O as the one observed in the LiCl and LiBr ICCs (see Figure 7, and compare with Figure 2d). The hydrogen bonding patterns are comparable, the only difference being the presence of an extra water molecule (on a special position with s.o.f. = 0.5 in the lattice), which bridges the water molecules coordinated to the lithium cations. As in the previous cases, the calculated powder pattern matches the experimental one (see Figure 8). The thermal analyses of the cocrystal showed a weight loss (ca. 7.9%) between 70 and 160 °C, associated with the complete dehydration of the sample. The variable temperature powder diffraction (see Figure S11) showed the change in the crystal structure associated with the dehydration process. The powder pattern is most likely that of the anhydrous ICC

Figure 3. Comparison between the experimental powder pattern of L-His·LiCl·H2O (top) and the one calculated from single crystal data (bottom). 7266



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which is unstable and rehydrates immediately when cooled to room temperature. The reaction of LiI with DL-histidine leads to chiral resolution and formation of a conglomerate made of crystals of L-His·LiI· 1.5H2O and of crystals of D-His·LiI·1.5H2O (see Scheme 4 for a pictorial representation), which are the same cocrystal as, and isomorphous with the L-His·LiI·1.5H2O ICC, obtained by reaction of enantiopure L-histidine with LiI. Figure 9 shows the identical PXRD patterns of the products obtained with

enantiopure and racemic histidine, indicating that in the case of a racemic conglomerate has formed. Salt-Induced Crystallization of the Monoclinic Form of Histidine. It is worth stressing that ionic cocrystal formation is not as simple as it may seem. In the context of this study we have attempted preparation of ICCs of L-histidine also with LiF, NaX, KX, RbX, CsBr, MgCl2, SrCl2 (X = Cl, Br), and only in the case of CaX2 (X = Cl, Br, I) it has been possible to obtain ICCs.

Figure 4. Experimental PXRD patterns for L-His·LiCl·H2O at room temperature (bottom) and at 210 °C (top). The pattern at 210 °C most likely represents the anhydrous ICC.

Figure 6. Comparison between the experimental powder pattern of DL-His·LiBr·1.5H2O (top) and the one calculated from single crystal data (bottom).

L-His·LiI,

DL-His·LiI·1.5H2O

Figure 5. (a) Projection in the bc-plane of an infinite chain of lithium coordination tetrahedra in crystalline DL-His·LiBr·1.5H2O (Owater in blue). (b) View of the crystal packing along the b-axis, showing alternate, enantiopure chains, here indicated in violet and orange, containing only L- or D-histidine ligands. (c) Superimposition of the L-chains observed in L-His·LiBr·H2O and the L-chains present in DL-His·LiBr·1.5H2O. 7267



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Scheme 3. A Pictorial Representation of the Racemic Crystal DL-His·LiCl/Br·1.5H2O as a “Cocrystal” Formed by L-His·LiCl/Br·H2O and D-His·LiCl/Br·H2O ICCs, with the Intervention of an Additional Water Molecule To “Glue” Them Together

Scheme 4. ICCs Formation between Histidine and LiI: (Top) L-His·LiI·1.5H2O is Obtained, with Essentially the Same Packing As Observed in L-His·LiCl·H2O and in L-His·LiBr; (Bottom) the Reaction of DL-Histidine with LiI Results in Chiral Resolution and Formation of a Racemic Conglomerate

Figure 7. Projection of crystalline L-His·LiI·1.5H2O in the ac-plane (Owater in blue; hydrogen bonds omitted for clarity).

Figure 9. Comparison between the calculated powder pattern of L-His· LiI·1.5H2O (bottom) and the one obtained by reaction of DL-His with LiI (top). The two patterns are superimposable, indicating that a racemic conglomerate has formed.

starting materials, led invariably to crystallization of L-histidine in its metastable polymorph, the monoclinic one.42 This is clearly observable in Figure 10 in the case of RbCl. The crystallization of the monoclinic form was quantitative from solutions containing NaCl, KCl, RbCl, RbBr, CsBr, MgCl2, and SrCl2, while crystallization from solutions of LiF, NaBr, and KBr yielded a mixture of the two polymorphs. The effect of change of polymorphism induced by an additive has been studied in a limited number of systems;56 one of the more striking cases is that of glycine,57 but this is the first time it is reported for L-histidine. The phenomenon is interesting and deserves a more systematic investigation.

Figure 8. Comparison between the experimental powder pattern of L-His·LiI·1.5H2O (top) and the one calculated from single crystal data (bottom).

The Ca2+ ICCs family is under investigation and will be reported in a subsequent paper under preparation. However, also the numerous, thus far, unsuccessful preparations yielded some interesting results. In fact the salts that did not afford ICCs, thus yielding a physical mixture of the 7268



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(VI) Water plays a crucial role, by completing the Li+ cation coordination sphere and “linking” chains together in the structure. Anhydrous compounds can be obtained by thermal treatment of the hydrates, although they are unstable and rehydrate quickly in the air at room temperature. (VII) In all its crystals the lithium cation shows a clear homochiral preference: the coordination selects histidine molecules of the same chirality in the DL-aggregates, both racemic and conglomerate, exactly of the same type observed in the enantiopure ICCs. The overall picture that emerges from these observations is intriguing. The racemic crystals DL-His·LiCl/Br·1.5H2O ought to be described as a kind of “cocrystal” formed by enantiopure L-His·LiCl/Br·H2O and D-His·LiCl/Br·H2O joined by water bridges. On the other hand, in the case of the product of the reaction of DL-His with LiI spontaneous chiral resolution takes place, leading to separation of the two enantiopure crystals L-His·LiI·1.5H2O and D-His·LiI·1.5H2O. The reasons for the homochiral preference of the lithium cation are under investigation.

Figure 10. Powder patterns comparison of the two polymorphic forms of L-His (in red the thermodynamically stable orthorhombic form, in blue the monoclinic form) and the one obtained by solution evaporation in the presence of RbCl (in black). The peak at 2θ = 23.4° is due to RbCl.

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CONCLUSIONS In this paper we have reported the preparation and characterization of a new family of ionic cocrystals obtained by reacting L-histidine and DL-histidine with LiCl, LiBr, and LiI. All the ICCs were prepared by kneading, and single crystals were obtained from aqueous solution by solvent evaporation. In all cases correspondence between the structure of the bulk polycrystalline materials obtained mechanochemically and the structures determined from single crystals was confirmed by comparing calculated and measured diffraction patterns. Both enantiopure and racemic ionic cocrystals were obtained in the form of hydrates. The dehydration processes were followed by thermogravimetric analysis and variable temperature powder diffraction, showing in all cases release of water and formation of crystalline anhydrous phases that rapidly rehydrated at room temperature when exposed to air. The idea behind this work was that of exploring the formation of ionic cocrystals in the case of racemic/enantiopure “competition”. The following observations can be made: (I) L- and DL-Histidine easily form ionic cocrystals with lithium halides, while no ICC formation has been observed thus far with larger alkali cations. (II) Crystals of L-His·LiCl·H2O and L-His·LiBr·H2O are isomorphous, as are those of DL-His·LiCl·1.5H2O and DL-His· LiBr·1.5H2O; preparation of solid solutions of these species can thus be envisaged.58−61 (III) The crystal structures of DL-His·LiCl·1.5H2O and + DL-His·LiBr·1.5H2O show that the Li cations selectively link to homochiral histidine molecules forming enantiopure chains of L-His·LiCl/D-His·LiCl and of L-His·LiBr/D-His·LiBr which pack in parallel fashion. (IV) The crystal of L-His·LiI·1.5H2O is not isomorphous with L-His·LiCl·H2O and L-His·LiBr·H2O, but contains the same tetrahedral coordination motif, with Li+ cations interacting with three L-histidines and one water molecule in spite of the difference in the total number of water molecules. (V) The X-ray powder pattern for the reaction product of DL-histidine with LiI, on the other hand, is superimposable with that of L-His·LiI·1.5H2O, indicating that chiral resolution has taken place leading to a racemic conglomerate of L-His·LiI· 1.5H2O and D-His·LiI·1.5H2O crystals; therefore the product obtained from DL-histidine and LiI ought to be formulated as a 50:50 mixture of L-His·LiI·1.5H2O and D-His·LiI·1.5H2O.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01426. Crystal structure details, TGA analyses, variable temperature PXRD patterns and the patterns for the saltinduced crystallization of the β-polymorph of histidine (PDF) Accession Codes

CCDC 1506017−1506020 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is financially supported by the University of Bologna and by industrial contracts. REFERENCES

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